Dementia of the Alzheimer's type is a chronic, progressive neurodegenerative process with attendant memory loss as the prominent early symptom, which may begin as early as in the 5th decade of life. With increasing life spans and aging of the population, AD is a great present and looming public health concern. In AD, acetylcholine transmitting neurons and their target nerve cells are affected. A current treatment to ameliorate the symptoms of AD is to increase the brain levels of neurotransmitter acetylcholine by inhibiting the activity of acetylcholinesterase (AChE), an enzyme which deacetylates and neutralizes the effect of beneficial levels of acetylcholine. Currently approved donepezil hydrochloride is such an agent.
A second mechanism to alleviate the symptoms of AD is to block the excitotoxic neuronal pathways related to excess glutamate release in the central nervous system (CNS). NMDA (N-methyl-D-aspartate) receptors are ionotropic receptors that mediate cellular transport of mono and divalent ions. It is known that excess Ca++ ions over normal levels of intracellular Ca++ ions results in neurotoxicity and cell death. Excessive excitation of NMDA receptors in the CNS needs to be moderated. [Jarvis, B., et al., Drugs Aging 20, 465-476 (2003).]
Memantine is a well-tolerated uncompetitive antagonist of NMDA receptors with moderate affinity towards these receptors. It is approved as an oral therapy for moderate to severe AD symptoms based on the results of a double-blind, placebo controlled study. [See Reisberg, B. et al., N. Engl. J. Med. 348, 1333-1341 (2003).] Memantine exerts neuroprotective effects in several models of brain injury in experimental animals. [See for example Parsons, C. G, et al., Neuropharmacology 38, 735-767 (1999); and Wilcock, G. K. Lancet Neurol. 2, 503-505 (2003).]
Published US 2005/0049312 A1 by F. Makovec, et al., describe preparation and uses of amidine derivatives of adamantanes with neuroprotective and antidepressant activities.
Recently, Hughes and Olejnik [in U.S. Patent Application 2003/0114460] described novel conjugates of memantine to enhance its use in ophthalmic applications which enhance the therapeutic disposition of the therapeutic component.
Levo carnitine (L-carnitine or vitamin BT) belongs to a class of water soluble vitamins which include vitamin B-12, folic acid, biotin, vitamin B-6, and mevalonic acid. L-acetyl carnitine has been shown to benefit Alzheimer's patients who are unresponsive to acetylcholinesterase inhibitors. [See, for example, Bianchetti, A. et al., Curr. Med. Res. Opin. 19, 350-353 (2003), Effects of acetyl-L-carnitine in Alzheimer's disease patients unresponsive to acetylcholinesterase inhibitors; Pettegrew, Jay W., et al., U.S. Patent Application 2005/272812, Method for the use of acetyl-L-carnitine for treatment of depressive disorders; and A. Spagnoli et al., Neurology 41, 1726-1732 (1991), Long-term acetyl-L-carnitine treatment in Alzheimer's disease.]
In view of the extensive literature devoted to the benefits of L-carnitine derivatives in the treatment of AD symptoms, the present invention uses novel conjugates of these compounds as esters and amides of adamantanamine and neramexane (1,3,3,5,5-cyclohexylamine) derivatives. Also the present invention describes a novel concept referred to as a “double prodrug” approach, which involves the preparation of novel covalent conjugates comprising two or more drugs, and their use in the treatment of various neurological and other disorders. A suitable covalent attachment of two or more of these agents, with or without a linker, will be of significant therapeutic value in that a single molecular entity may have multiple therapeutic effects resulting from diverse, but synergistic mechanisms of action, and controlled release of both drugs in vivo through enzymatic hydrolysis of the conjugate. The concept of the present invention is not limited to only CNS disorders; other therapeutic applications, including cardiovascular, diabetes, cancer, inflammation, and the like are also contemplated. In particular, the compounds of the present invention provide novel and useful linkers to conjugate with numerous drugs useful for treating the diseases of the eye.